Healthy humans normally breathe mostly through the nose, whereby the upper airways and especially the nasal cavity serves to regulate the temperature and humidity of the inhaled air. But the upper airways do not only function as an ingenious heat exchanger and humidifier; they are also thought to be the source of endogenous, biologically active agents, such as endogenous nitric oxide (NO).
Nitric oxide (NO) is synthesized from the amino acid arginine by specific enzymes (NO-synthase) present in many cell types in the human body. Endogenous NO is thought to play a key role as an effector molecule with many biological effects including vasodilatation, neurotransmission and host defence. The biological effects of NO are mostly attributed to its rapid reaction with certain iron-containing enzymes resulting in either activation or inactivation of the enzyme. For example, NO produced in vascular endothelium diffuses to smooth muscle cells and binds to the heme moiety of soluble guanylate cyclase resulting in activation of the enzyme, formation of cyclic GMP and subsequently vasodilatation. NO produced by e.g. activated macrophages, may also have bacteriostatic and antiviral properties, thereby contributing to unspecific host defense.
Inhalation of exogenous NO gas has been used to reduce pulmonary vascular resistance in subjects with pulmonary hypertension. NO acts as a dilator of the pulmonary circulation when administered by the inhalation route. As soon as NO reaches the circulation it reacts with e.g. haemoglobin and is inactivated. Thus, NO may act selectively on pulmonary and bronchial circulation without affecting systemic circulation. Clinical trials are presently performed to explore the clinical outcome of exogenous NO inhalation in the treatment of certain pulmonary vascular disorders.
It is essential to handle exogenous NO with extreme caution, since high doses may be very dangerous, even lethal. NO reacts rapidly with oxygen to form NO.sub.2. Higher doses of NO.sub.2 may result in delayed haemorrhagic pulmonary edema. Furthermore, high concentrations of inhaled NO may result in methaemoglobinaemia due to competitive interaction with oxygen binding to haemoglobin.
Due to the above mentioned dangers of exogenous NO, it is vital to most carefully monitor the amounts of NO and NO.sub.2 in inhaled air of patients receiving inhalation NO therapy. This may be carried out by connecting a NO/NO.sub.2 analyzer (e.g. an apparatus using chemiluminescence technique) for on-line registration of NO/NO.sub.2 concentrations in the inspirational airflow leaving the ventilator and distributed to the patient. Additionally, due to the rapid reaction of NO with oxygen, compressed NO gas must be kept in gas bottles free from oxygen. The gas administered to the patient should also be led through NO.sub.2 scavenging arrangements, such as containers with soda lime.
The guidelines concerning therapeutic use of NO, issued by the Swedish Medical Products Agency (Lakemedelsverkets riktlinjer for anvandning av kvavemonoxid p.ang. licens i samband med ventilator be handling, Apr. 25, 1995) emphasize the risks associated with formation of NO.sub.2. Acute toxic effects are known and possible mutagenic effects can not be ruled out. The guidelines specify that the concentration of NO.sub.2 in the inspiratory flow must be guaranteed to be less than 2 ppm at all times. Strict monitoring requirements are laid out, including continuous monitoring of the oxygen concentration in the inspiratory gasflow; continuous percutaneous oximetry, arterial blood gas analyses including oxygen saturation; monitoring of central venous blood pressure; and determinations of blood methaemoglobin at least twice daily and for children under one year of age, at least four times daily.
In the prior art a blend of NO in N.sub.2 is used with NO at concentrations of approximately 100 to 1000 ppm. Oxygen-free NO is mixed with air and thereby diluted to the desired final concentration immediately before administration to the patient. A flow controller should be used to achieve an appropriate blend of NO and air. All equipment should be regularly calibrated and a manual backup system should be available. To avoid risk to personnel working with NO inhalation therapy NO bottles should be kept in a well-ventilated room.
In all published reports of NO-inhalation therapy, an exogenous source has been used and the reports contain mentions of the safety precautions taken.
WO 92/10228 discloses an inhaler device for administering NO to a patient, said device comprising a vessel containing pressurized gas comprising at least 1 ppm NO; a housing defining a lumen, said vessel being attached to said housing to deliver said gas into said lumen; and a mechanism for controllably releasing said gas from said vessel into said lumen; said lumen being configurated to route said released gas into the respiratory system of a person, and said device weighing less than approximately 5 kg. In the description only exogenous sources of NO are mentioned and the NO is said to be administered in concentrations ranging from 1 to 40 ppm and momentarily even increased to 80-180 ppm.
Further WO 91/14469 describes an apparatus and method for selective, separate or simultaneous collection and analysis of nasal and oral gases, respired by a patient, with optional simultaneous delivery to the patient of selected inhalant gases. The apparatus is specifically constructed and arranged to avoid or minimize contact with the patients's mouth or other facial surfaces. This is obviously far from the applications concerned in the present invention, that is collecting endogenous gases, in particular NO and supplying the same gases to an intubated or tracheostomized patient through the inhalatory flow of a ventilator. WO 91/14469 mentions the collection and analysis of various exhaled gases and, additionally the administration of oxygen or air, or a mixture of oxygen and air or of oxygen and water vapour and anaesthetic gases. No mention of administering an endogenous gas back to the patient can be found in the description or claims.
It is known that NO is endogenously produced in the upper airways of healthy subjects. NO is normally present in nasal air at concentrations ranging from 0, 1 to 5 ppm. The present inventors have found that the synthesis of NO in the upper airways is mostly carried out by a high producing "inducible like" NO synthase (NOS) situated in the epithelial cells of the paranasal sinuses. NO is probably also produced in the nasal cavity and in the nasopharynx. The present inventors have found that sinus derived air normally enters the nasal cavity through the ducts connecting the sinuses with the nose and is a large contributor to NO found in nasally exhaled air. In contrast, NO excretion in the lower airways and the lungs seems to be very low since tracheostomized patients exhibit only low NO levels when exhaling through the tracheostomy. Furthermore the high producing "inducible like" NOS described in normal paranasal sinuses is not normally present in the lower airways of healthy subjects. NO produced in the upper airways not only follows the airstream out with every exhalation but also flows down to the lower airways and lungs with every inhalation. Therefore a continuous low-dose NO flushing of the lower airways takes place normally in healthy subjects. However, patients with an endotracheal tube or tracheostomy are deprived of this self administration of NO since the upper airways, where most of airway NO production takes place, are by-passed by the intubation manoeuvre.
It is contemplated that also other endogenous agents, for example other gases or other endogenous, systemic or locally active agents, are synthesized in the upper airways. These agents can be any biologically active agent or agents, chosen from the group including hormones, enzymes, substrates, large molecular proteins, fractionated proteins, in the form of aerosols, droplets or gases. Patients with an endotracheal tube or tracheostomy are however deprived of the beneficial effects of these endogenous, biologically active agents. This can be especially significant in intubated or tracheostomized children, who normally breath almost exclusively through the nose.